Chemical and Structural Biology Research Program: Project Summary The Chemical and Structural Biology (CSB) Program makes use of a wide range of chemical, biochemical and structural approaches to investigate the underlying mechanisms involved in cancer, identify unique biological targets for cancer chemotherapy, and develop potential chemical approaches to cancer treatments. CSB Program members represent Purdue University foundational strengths in structural biology, chemistry, medicinal chemistry, pharmacy and the biological sciences. Specifically, the CSB Program is comprised of 18 members, from 4 Purdue University academic departments and 3 different colleges. These highly collaborative CSB investigators published 279 papers since the last review in 2010, with 23 (8%) of these involving intra- programmatic collaborative efforts, 43 (15%) representing inter-programmatic research activities, and 24 (9%) inter-institutional publications, providing an overall collaborative record of nearly one third of the total (32%). These efforts are sustained by $4.9M (direct costs) of cancer-related, peer-reviewed, extramural grant support. Fundamental and technical advances in chemistry, biochemistry, and structural and molecular biology over the past several decades have provided unprecedented opportunities to probe the living systems involved in cancer at a molecular level. The complementary, multidisciplinary approaches in this program result in strong collaborative efforts that focus research groups into effective subgroup teams. Research Clusters in the CSB Program include: (1) Intracellular Signaling Pathways and Cancer, (2) Membrane Proteins in Cancer, and (3) Chemical and Biophysical Tools to Probe Molecules Involved in Human Cancer. These Research Clusters use a variety of approaches to foster discovery. Structural biology approaches allow Program members to address the molecular mechanism of target molecules using high resolution NMR, X-ray crystallography, cryoelectron microscopy and a supporting array of biophysical techniques. By developing a structural understanding of these molecules and their interactions, they provide a framework on which mutations and posttranslational modifications associated with cancer can be understood and from which new potential inhibitors can be developed. In this Research Program, proteomic analysis can first define these critical molecular targets and then researchers can explore epigenetic variations and response to cellular signaling that can provide the basis for modern molecular medicine approaches to cancer. Chemical biology provides another highly effective approach for identifying these critical targets and probing their biochemical details in a high- throughput fashion. By applying groundbreaking chemical methodology, this area of research can drive the development of unique chemical entities that complement the research being done in basic biological investigations, therapeutics development, and imaging efforts in the other three Research Programs of the Purdue University Center for Cancer Research (PCCR).